Benzimidazole derivatives useful as TRPM8 channel modulators

ABSTRACT

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds are represented by Formula I as follows: 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 0 , R 1 , R 2 , R 3 , R 4  and a are defined herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application61/185,686, filed on Jun. 10, 2009, which is incorporated by referenceherein in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The research and development of the invention described below was notfederally sponsored.

FIELD OF THE INVENTION

The present invention is directed to benzimidazole derivatives,pharmaceutical compositions containing them and their use in thetreatment of disorders and conditions modulated by the TRPM8 (transientreceptor potential melastatin subfamily type 8) channel. The presentinvention also relates to processes for the preparation of benzimidazolederivatives and to their use in treating various diseases, syndromes,and disorders, including, those that cause inflammatory pain,neuropathic pain, cardiovascular diseases aggravated by cold, pulmonarydiseases aggravated by cold, and combinations thereof.

BACKGROUND OF THE INVENTION

Transient receptor potential (TRP) channels are non-selective cationchannels that are activated by a variety of stimuli. Numerous members ofthe ion channel family have been identified to date, including thecold-menthol receptor, also called TRPM8 (McKemy D. D., et al., Nature2002, 416(6876), 52-58). Collectively, the TRP channels and relatedTRP-like receptors connote sensory responsivity to the entire continuumof thermal stimulation, selectively responding to threshold temperaturesranging from noxious hot through noxious cold as well as to certainchemicals that mimic these sensations. Specifically, TRPM8 is known tobe stimulated by cool to cold temperatures as well as by chemical agentssuch as menthol and icilin, which may be responsible for the therapeuticcooling sensation that these agents provoke.

TRPM8 is located on primary nociceptive neurons (A-δ and C-fibers) andis also modulated by inflammation-mediated second messenger signals(Abe, J., et al., Neurosci Lett 2006, 397(1-2), 140-144; Premkumar, L.S., et al., J. Neurosci, 2005, 25(49), 11322-11329). The localization ofTRPM8 on both A-δ and C-fibers may provide a basis for abnormal coldsensitivity in pathologic conditions wherein these neurons are altered,resulting in pain, often of a burning nature (Kobayashi, K., et al., JComp Neurol, 2005, 493(4), 596-606; Roza, C., et al., Pain, 2006,120(1-2), 24-35; and Xing, H., et al., J Neurophysiol, 2006, 95(2),1221-30). Cold intolerance and paradoxical burning sensations induced bychemical or thermal cooling closely parallel symptoms seen in a widerange of clinical disorders and thus provide a strong rationale for thedevelopment of TRPM8 modulators as novel antihyperalgesic orantiallodynic agents. TRPM8 is also known to be expressed in brain,lung, bladder, gastrointestinal tract, blood vessels, prostate andimmune cells, thereby providing the possibility for therapeuticmodulation in a wide range of maladies.

There is a need in the art for TRPM8 antagonists that can be used totreat a disease, syndrome, or condition in a mammal in which thedisease, syndrome, or condition is affected by the modulation of TRPM8channels, such as pain, the diseases that lead to such pain, andpulmonary or vascular dysfunction.

SUMMARY OF THE INVENTION

The present invention is directed to, inter alia, compounds of formula(I)

wherein

a is an integer from 0 to 3;

each R⁰ is independently selected from the group consisting of halogen,hydroxy, cyano, lower alkyl, fluorinated lower alkyl, lower alkoxy andfluorinated lower alkoxy;

R² is selected from the group consisting of hydrogen, halogen, hydroxy,cyano, lower alkyl, fluorinated lower alkyl, lower alkoxy andfluorinated lower alkoxy;

R¹ is selected from the group consisting of alkyl, hydroxy substitutedlower alkyl, halogenated lower alkyl, cycloalkyl-(lower alkyl)- andphenyl-(lower alkyl)-;

alternatively R² and R¹ are taken together as

(i.e. as —O—CH₂—CH₂—) or

(i.e. as —CH₂—CH₂—CH₂—);

R³ is selected from the group consisting of lower alkyl, cycloalkyl,aryl, heteroaryl, heterocycloalkyl, cycloalkyl-(lower alkyl)-,aryl-(lower alkyl)-, heteroaryl-(lower alkyl)- andheterocycloalkyl-(lower alkyl)-;

wherein the cycloalkyl, aryl, heteroaryl or heterocycloalkyl, whetheralone or as part of a substituent group, is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, lower alkyl, halogenated lower alkyl, loweralkoxy, halogenated lower alkoxy, —C(O)OH, —C(O)O-(lower alkyl) and—C(O)—NR^(A)R^(B);

wherein R^(A) and R^(B) are each independently selected from the groupconsisting of hydrogen and lower alkyl; alternatively R^(A) and R^(B)are taken together with the nitrogen atom to which they are bound toform a 5 to 6 membered, saturated nitrogen containing ring structure;

R⁴ is selected from the group consisting of lower alkyl, cycloalkyl,aryl, heteroaryl, heterocycloalkyl, cycloalkyl-(lower alkyl)-,aryl-(lower alkyl)-, heteroaryl-(lower alkyl)- andheterocycloalkyl-(lower alkyl)-;

wherein the cycloalkyl, aryl, heteroaryl or heterocycloalkyl, whetheralone or as part of a substituent group, is optionally substituted withone or more substituents independently selected from the groupconsisting of halogen, lower alkyl, halogenated lower alkyl, loweralkoxy, halogenated lower alkoxy and —S—CF₃;

provided that when R⁴ is heteroaryl or heterocycloalkyl, then the R⁴group is bound to the N of the compound of formula (I) through a carbonatom;

and solvates, hydrates and pharmaceutically acceptable salts thereof.

The present invention is further directed to processes for thepreparation of the compounds of formula (I). The present invention isfurther directed to a product prepared according to the processdescribed herein.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and the product prepared accordingto the process described herein. An illustration of the invention is apharmaceutical composition made by mixing the product prepared accordingto the process described herein and a pharmaceutically acceptablecarrier. Illustrating the invention is a process for making apharmaceutical composition comprising mixing the product preparedaccording to the process described herein and a pharmaceuticallyacceptable carrier.

Exemplifying the invention are methods of treating a disorder modulatedby TRPM8 (selected from the group consisting of inflammatory pain(including visceral pain), neuropathic pain (including neuropathic coldallodynia), cardiovascular disease aggravated by cold and pulmonarydisease aggravated by cold, in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of anyof the compounds or pharmaceutical compositions described above.

Another example of the invention is the use of any of the compoundsdescribed herein in the preparation of a medicament wherein themedicament is prepared for treating: (a) inflammatory pain, (b)neuropathic pain, (c) cardiovascular disease aggravated by cold, or (d)pulmonary disease aggravated by cold, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a process for the preparation ofcompound of formula (I)

wherein a, R⁰, R¹, R², R³ and R⁴ are as herein defined, andpharmaceutically acceptable salts thereof The compounds of the presentinvention are useful in the treatment of disorders mediated by TRP M8,including inflammatory pain (including visceral pain), inflammatoryhyperalgesia, neuropathic pain (including neuropathic cold allodynia),inflammatory somatic hyperalgesia, inflammatory visceral hyperalgesia,cardiovascular disease aggravated by cold and pulmonary diseaseaggravated by cold.

In an embodiment of the present invention, a is an integer from 0 to 2.In another embodiment of the present invention, a is an integer from 0to 1. In another embodiment of the present invention, a is an integerform 1 to 2. In another embodiment of the present invention, a is 0.

In an embodiment of the present invention, each R⁰ is selected from thegroup consisting of halogen, lower alkyl, fluorinated lower alkyl, loweralkoxy and fluorinated lower alkoxy. In another embodiment of thepresent invention, each R⁰ is selected from the group consisting ofhalogen, C₁₋₂alkyl and fluorinated C₁₋₂alkyl. In another embodiment ofthe present invention, each R⁰ is selected from the group consisting offluoro, chloro, methyl and trifluoromethyl. In another embodiment of thepresent invention, each R⁰ is independently selected from the groupconsisting of fluoro, chloro and methyl. In another embodiment of thepresent invention, each R⁰ is independently selected from the groupconsisting of fluoro and methyl.

In another embodiment of the present invention, each R⁰ is independentlyselected from the group consisting of fluoro, chloro andtrifluoromethyl. In another embodiment of the present invention, each R⁰is independently selected from the group consisting of chloro andtrifluoromethyl. In an embodiment of the present invention, the R⁰ groupis bound at the 4-, 5- and/or 6-position of the benzimidazole core. Inanother embodiment of the present invention, the R⁰ group is bound atthe 5- and/or 6-position of the benzimidazole core.

In an embodiment of the present invention, R² is selected from the groupconsisting of hydrogen, halogen, lower alkyl, fluorinated lower alkyl,lower alkoxy and fluorinated lower alkoxy. In another embodiment of thepresent invention, R² is hydrogen. In another embodiment of the presentinvention, R² is selected from the group consisting of hydrogen,halogen, lower alkyl and fluorinated lower alkyl.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of alkyl, hydroxy substituted lower alkyl, fluorinated loweralkyl, cycloalkyl-(lower alkyl)- and phenyl-(lower alkyl)-. In anotherembodiment of the present invention, R¹ is selected from the groupconsisting of lower alkyl, hydroxy substituted lower alkyl, fluorinatedlower alkyl, monocyclic cycloalkyl-(lower alkyl)- and phenyl-(loweralkyl)-.

In an embodiment of the present invention, R¹ is selected from the groupconsisting of alkyl, hydroxy substituted lower alkyl, fluorinated loweralkyl, monocyclic cycloalkyl-(lower alkyl)- and phenyl-(lower alkyl)-.In another embodiment of the present invention, R¹ is selected from thegroup consisting of lower alkyl, fluorinated lower alkyl and monocycliccycloalkyl-(lower alkyl)-.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of methyl, ethyl, isopropyl, isobutyl,1-(2-hydroxy-ethyl), 1-(2,2,2-trifluoroethyl), benzyl andcyclopropyl-methyl-. In another embodiment of the present invention, R¹is selected from the group consisting of methyl, ethyl and isopropyl. Inanother embodiment of the present invention, R¹ is selected from thegroup consisting of methyl and ethyl. In another embodiment of thepresent invention, R¹ is methyl.

In another embodiment of the present invention, R¹ is selected from thegroup consisting of methyl, ethyl, isopropyl, isobutyl,1-(2,2,2-trifluoroethyl) and cyclopropyl-methyl-. In another embodimentof the present invention, R¹ is selected from the group consisting ofmethyl, ethyl, isopropyl, 1-(2,2,2,-trifluoroethyl) andcyclopropyl-methyl-. In another embodiment of the present invention, R¹is selected from the group consisting of methyl, ethyl, isopropyl and1-(2,2,2-trifluoro-ethyl).

In an embodiment of the present invention, R² and R¹ are taken togetheras

In another embodiment of the present invention, R² and R¹ are takentogether as

In another embodiment of the present invention, R² and R¹ are takentogether as

In an embodiment of the present invention, R³ is selected from the groupconsisting of lower alkyl, monocyclic cycloalkyl, phenyl, monocyclicheteroaryl, monocyclic heterocycloalkyl, monocyclic cycloalkyl-(loweralkyl)-, phenyl-(lower alkyl)-, monocyclic heteroaryl-(lower alkyl)- andmonocyclic heterocycloalkyl-(lower alkyl)-; wherein the monocycliccycloalkyl, phenyl, monocyclic heteroaryl or monocyclicheterocycloalkyl, whether alone or as part of a substituent group, isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, lower alkyl, fluorinatedlower alkyl, lower alkoxy, fluorinated lower alkoxy, —C(O)OH,—C(O)O-(lower alkyl) and —C(O)—NR^(A)R^(B); and wherein R^(A) and R^(B)are each independently selected from the group consisting of hydrogenand lower alkyl. In another embodiment of the present invention, R³ isselected from the group consisting of lower alkyl, monocycliccycloalkyl, phenyl, monocyclic cycloalkyl-(lower alkyl)- andphenyl-(lower alkyl)-; wherein the monocyclic cycloalkyl or phenyl,whether alone or as part of a substituent group, is optionallysubstituted with one or to two substituents independently selected fromthe group consisting of halogen, lower alkyl, fluorinated lower alkyl,lower alkoxy and fluorinated lower alkoxy. In another embodiment of thepresent invention, R³ is selected from the group consisting of loweralkyl and phenyl; wherein the phenyl is optionally substituted with asubstituent selected from the group consisting of halogen, lower alkyland fluorinated lower alkyl. In another embodiment of the presentinvention, R³ is phenyl; wherein the phenyl is optionally substitutedwith a substituent selected from the group consisting of halogen andfluorinated lower alkyl.

In another embodiment of the present invention, R³ is selected from thegroup consisting of methyl, phenyl, 3-chlorophenyl, 4-chlorophenyl,4-fluorophenyl, 4-methylphenyl and 4-trifluoromethylphenyl. In anotherembodiment of the present invention, R³ is selected from the groupconsisting of methyl, phenyl, 4-fluorophenyl, 4-chlorophenyl and4-methylphenyl. In another embodiment of the present invention, R³ isselected from the group consisting of methyl, phenyl, 4-fluorophenyl and4-chlorophenyl. In another embodiment of the present invention, R³ isphenyl. In another embodiment of the present invention, R³ is selectedfrom the group consisting of phenyl, 4-fluorophenyl, 4-chlorophenyl and4-trifluoromethylphenyl. In another embodiment of the present invention,R³ is phenyl.

In an embodiment of the present invention, R⁴ is selected from the groupconsisting of lower alkyl, monocyclic cycloalkyl, phenyl, monocyclicheteroaryl, monocyclic heterocycloalkyl, monocyclic cycloalkyl-(loweralkyl)-, phenyl-(lower alkyl)-, monocyclic heteroaryl-(lower alkyl)- andmonocyclic heterocycloalkyl-(lower alkyl)-; wherein the monocycliccycloalkyl, phenyl, monocyclic heteroaryl or monocyclicheterocycloalkyl, whether alone or as part of a substituent group, isoptionally substituted with one to two substituents independentlyselected from the group consisting of halogen, lower alkyl, fluorinatedlower alkyl, lower alkoxy, fluorinated lower alkoxy and —S—CF₃. Inanother embodiment of the present invention, R⁴ is selected from thegroup consisting of lower alkyl, monocyclic cycloalkyl, phenyl,monocyclic cycloalkyl-(lower alkyl)- and phenyl-(lower alkyl)-; whereinthe monocyclic cycloalkyl or phenyl, whether alone or as part of asubstituent group, is optionally substituted with one to twosubstituents independently selected from the group consisting ofhalogen, lower alkyl, fluorinated lower alkyl, lower alkoxy, fluorinatedlower alkoxy and —S—CF₃. In another embodiment of the present invention,R⁴ is selected from the group consisting of lower alkyl andphenyl-(lower alkyl); wherein the phenyl portion of the phenyl-(loweralkyl)-group is optionally substituted with one to two substituentsindependently selected from the group consisting of halogen, fluorinatedlower alkyl, fluorinated lower alkoxy and —S—CF₃. In another embodimentof the present invention, R⁴ is phenyl-(lower alkyl); wherein the phenylportion of the phenyl-lower alkyl)-group is optionally substituted withone to two substituents independently selected from the group consistingof halogen, fluorinated lower alkyl, fluorinated lower alkoxy and—S—CF₃. In another embodiment of the present invention, R⁴ is selectedfrom the group consisting of methyl, n-butyl, benzyl, 4-chlorophenyl,4-fluoro-benzyl, 3,4-difluoro-benzyl, 3-chloro-4-fluoro-benzyl,3-trifluoromethyl-benzyl, 4-trifluoromethyl-benzyl,3-trifluoromethoxy-benzyl, 4-trifluoromethoxy-benzyl,3-trifluoromethyl-4-fluoro-benzyl, 3-fluoro-4-trifluoromethyl-benzyl,2-fluoro-5-trifluoromethyl-benzyl, 4-difluoromethoxy-benzyl and4-trifluoromethyl-thio-benzyl. In another embodiment of the presentinvention, R⁴ is selected from the group consisting of n-butyl, benzyl,4-fluoro-benzyl, 3,4-difluoro-benzyl, 3-trifluoromethyl-benzyl,4-trifluoromethyl-benzyl, 4-difluoromethoxy-benzyl,3-trifluoromethoxy-benzyl, 4-trifluoromethoxy-benzyl,3-chloro-4-fluoro-benzyl, 3-trifluoromethyl-4-fluoro-benzyl,3-fluoro-4-trifluoromethyl-benzyl, 2-fluoro-5-trifluoromethyl-benzyl and4-trifluoromethyl-thio-benzyl. In another embodiment of the presentinvention, R⁴ is selected from the group consisting of benzyl,4-fluoro-benzyl, 3,4-difluoro-benzyl, 3-trifluoromethyl-benzyl,4-trifluoromethyl-benzyl, 4-difluoromethoxy-benzyl,3-trifluoromethoxy-benzyl, 4-trifluoromethoxy-benzyl,3-chloro-4-fluoro-benzyl, 3-trifluoromethyl-4-fluoro-benzyl,3-fluoro-4-trifluoromethyl-benzyl, 2-fluoro-5-trifluoromethyl-benzyl and4-trifluoromethyl-thio-benzyl. In another embodiment of the presentinvention, R⁴ is selected from the group consisting of 4-fluoro-benzyl,3,4-difluoro-benzyl, 3-trifluoromethyl-benzyl, 4-trifluoromethyl-benzyl,4-difluoromethoxy-benzyl, 3-trifluoromethoxy-benzyl,4-trifluoromethoxy-benzyl, 3-chloro-4-fluoro-benzyl,3-trifluoromethyl-4-fluoro-benzyl, 3-fluoro-4-trifluoromethyl-benzyl and4-trifluoromethyl-thio-benzyl.

In another embodiment of the present invention, R⁴ is selected from thegroup consisting of benzyl, 4-fluoro-benzyl, 3,4-difluoro-benzyl,3-chloro-4-fluoro-benzyl, 4-difluoromethyl-benzyl,3-trifluoromethyl-benzyl, 4-trifluoromethyl-benzyl,3-trifluoromethoxy-benzyl, 4-trifluoromethoxy-benzyl,3-fluoro-4-trifluoromethyl-benzyl, 3-trifluoromethyl-4-fluoro-benzyl,2-fluoro-5-trifluoromethyl-benzyl and 4-trifluoromethyl-thio-benzyl. Inanother embodiment of the present invention, R⁴ is selected from thegroup consisting of 3-chloro-4-fluoro-benzyl, 3-trifluoromethyl-benzyl,4-trifluoromethyl-benzyl, 3-trifluoromethoxy-benzyl,4-trifluoromethoxy-benzyl, 3-fluoro-4-trifluoromethyl-benzyl and2-fluoro-5-trifluoromethyl-benzyl. In another embodiment of the presentinvention, R⁴ is selected from the group consisting of4-trifluoromethyl-benzyl, 4-trifluoromethoxy-benzyl and3-fluoro-4-trifluoromethyl-benzyl.

In an embodiment of the present invention, R⁴ is other than methyl. Inanother embodiment of the present invention, R⁴ is other than loweralkyl.

Additional embodiments of the present invention, include those whereinthe substituents selected for one or more of the variables definedherein (i.e. a, R⁰, R¹, R², R³ and R⁴) are independently selected to beany individual substituent or any subset of substituents selected fromthe complete list as defined herein. In another embodiment of thepresent invention is any single compound or subset of compounds selectedfrom the representative compounds listed in Tables 1 and 2, below.Representative compounds of the present invention are as listed inTables 1 and 2, below.

TABLE 1 Representative Compounds of Formula (I)

ID No (R⁰)_(a) R¹ R³ R⁴ 1 a = 0 benzyl phenyl n-butyl 2 a = 0—CH₂—CH₂—OH phenyl n-butyl 3 a = 0 methyl 4-methyl- methyl phenyl 4 a =0 methyl phenyl n-butyl 6 a = 0 methyl phenyl 4-trifluoromethoxy- benzyl8 a = 0 methyl phenyl 4-fluoro-benzyl 9 a = 0 methyl phenyl3,4-difluoro-benzyl 10 a = 0 methyl phenyl benzyl 11 a = 0 methyl phenyl4-trifluoromethyl- benzyl 12 a = 0 methyl phenyl 3-trifluoromethyl-benzyl 13 a = 0 methyl phenyl 3-trifluoromethoxy- benzyl 14 a = 0 methyl3-chloro- 3-trifluoromethyl-4- phenyl fluoro-benzyl 15 a = 0 methylphenyl 3-trifluoromethyl-4- fluoro-benzyl 17 a = 0 methyl methyl3-trifluoromethyl-4- fluoro-benzyl 18 a = 0 methyl 4-methyl-3-trifluoromethyl-4- phenyl fluoro-benzyl 19 a = 0 methyl phenyl4-trifluoromethyl- thio-benzyl 20 a = 0 methyl phenyl 3-chloro-4-fluoro-benzyl 21 a = 0 methyl phenyl 3-fluoro-4- trifluoromethyl- benzyl 22 a =0 methyl phenyl 2-fluoro-5- trifluoromethyl- benzyl 23 a = 0 methylphenyl 4-difluoromethoxy- benzyl 24 a = 0 isobutyl phenyl4-trifluoromethyl- benzyl 26 a = 0 methyl 4-chloro- 4-trifluoromethoxy-phenyl benzyl 27 a = 0 methyl 4- 4-trifluoromethoxy- trifluoro- benzylmethyl- phenyl 28 a = 0 methyl 4-fluoro- 4-trifluoromethyl- phenylbenzyl 29 a = 0 ethyl phenyl 4-trifluoromethoxy- benzyl 30 a = 0 ethylphenyl 4-trifluoromethyl- benzyl 31 a = 0 methyl 4- 4-trifluoromethyl-trifluoro- benzyl methyl- phenyl 32 a = 0 methyl 4-fluoro-4-trifluoromethoxy- phenyl benzyl 33 6-trifluoro- methyl phenyl4-trifluoromethoxy- methyl benzyl 34 a = 0 ethyl phenyl 3-fluoro-4-trifluoromethyl- benzyl 35 6-trifluoro- methyl phenyl 3-fluoro-4- methyltrifluoromethyl- benzyl 36 a = 0 methyl phenyl 4-chlorophenyl 376-trifluoro- methyl phenyl 4-trifluoromethyl- methyl benzyl 38 a = 0methyl 4-fluoro- 3-fluoro-4- phenyl trifluoromethyl- benzyl 39 a = 0methyl 4-chloro- 3-fluoro-4- phenyl trifluoromethyl- benzyl 40 a = 0methyl 4- 3-fluoro-4- trifluoro- trifluoromethyl- methyl- benzyl phenyl41 a = 0 methyl 4-chloro- 4-trifluoromethyl- phenyl benzyl 425-trifluoro- ethyl phenyl 3-fluoro-4- methyl trifluoromethyl- benzyl 435-fluoro methyl phenyl 4-trifluoromethyl- benzyl 44 5-trifluoro-isopropyl phenyl 4-trifluoromethoxy- methyl benzyl 45 5-trifluoro-isopropyl phenyl 3-fluoro-4- methyl trifluoromethyl- benzyl 46 5-fluoroethyl phenyl 4-trifluoromethoxy- benzyl 47 5-fluoro ethyl phenyl4-trifluoromethyl- benzyl 48 5-fluoro ethyl phenyl 3-fluoro-4-trifluoromethyl- benzyl 49 a = 0 isobutyl phenyl 4-trifluoromethoxy-benzyl 50 a = 0 isobutyl phenyl 3-fluoro-4- trifluoromethyl- benzyl 515-trifluoro- methyl phenyl 4-trifluoromethyl- methyl benzyl 525-trifluoro- methyl phenyl 4-trifluoromethoxy- methyl benzyl 535-trifluoro- methyl phenyl 3-fluoro-4- methyl trifluoromethyl- benzyl 54a = 0 1-(2,2,2- phenyl 4-trifluoromethyl- trifluoroethyl) benzyl 565-chloro isopropyl phenyl 3-fluoro-4- trifluoromethyl- benzyl 575-fluoro methyl phenyl 4-trifluoromethoxy- benzyl 58 5-fluoro methylphenyl 3-fluoro-4- trifluoromethyl- benzyl 59 a = 0 1-(2,2,2- phenyl4-trifluoromethoxy- trifluoroethyl) benzyl 60 a = 0 1-(2,2,2- phenyl3-fluoro-4- trifluoroethyl) trifluoromethyl- benzyl 61 5-chloroisopropyl phenyl 4-trifluoromethoxy- benzyl 66 6-methyl methyl phenyl4-trifluoromethoxy- benzyl 67 6-methyl methyl phenyl 3-fluoro-4-trifluoromethyl- benzyl 68 6-methyl methyl phenyl 4-trifluoromethyl-benzyl 69 a = 0 cyclopropyl- phenyl 4-trifluoromethoxy- methyl- benzyl70 a = 0 cyclopropyl- phenyl 4-trifluoromethyl- methyl- benzyl 71 a = 0cyclopropyl- phenyl 3-fluoro-4- methyl- trifluoromethyl- benzyl 74 5,6-methyl phenyl 4-trifluoromethoxy- dimethyl benzyl 75 5,6- methyl phenyl3-fluoro-4- dimethyl trifluoromethyl- benzyl 76 4-methyl methyl phenyl3-fluoro-4- trifluoromethyl- benzyl

TABLE 2 Representative Compounds of Formula (I)

ID No —R² + R¹— R³ R⁴ 62

phenyl 4-trifluoromethoxy- benzyl 63

phenyl 3-fluoro-4- trifluoromethyl-benzyl 65

phenyl 4-trifluoromethyl-benzyl 72

phenyl 4-trifluoromethyl-benzyl 73

phenyl 4-trifluoromethoxy- benzyl

In an embodiment, the present invention is directed to a compound offormula (I) which exhibits a % Inhibition at 0.2 μM of greater than orequal to about 10% (preferably greater than or equal to about 25%, morepreferably greater than or equal to about 50%, more preferably greaterthan or equal to about 80%), as measured according to the proceduredescribed in Biological Example 1, which follows herein. In anembodiment, the present invention is directed to a compound of formula(I) which exhibits an IC₅₀ of less than or 0.100 μM, preferably lessthan or equal to about 0.050 μM, more preferably less than or equal toabout 0.025 μM, more preferably less than or equal to about 0.010 μM,more preferably less than or equal to about 0.005 μM, as measuredaccording to the procedure described in Biological Example 1, whichfollows herein.

As used herein, unless otherwise noted, the term “halogen” refers tochlorine, bromine, fluorine and iodine.

As used herein, unless otherwise noted, the term “alkyl” whether usedalone or as part of a substituent group, include straight and branchedchains having 1 to 8 carbon atoms. Therefore, designated numbers ofcarbon atoms (e.g. C₁₋₈) refer independently to the number of carbonatoms in an alkyl moiety or to the alkyl portion of a largeralkyl-containing substituent. In substituent groups with multiple alkylgroups such as (C₁₋₆alkyl)₂amino- the C₁₋₆alkyl groups of thedialkylamino may be the same or different. For example, alkyl radicalsinclude methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,t-butyl, pentyl and the like. Unless otherwise noted, the term “lower”when used with alkyl means a carbon chain having 1-4 carbon atoms.

As used herein, unless otherwise noted, the term “halogenated loweralkyl” refers to any lower alkyl group as defined above substituted withat least one halogen atom, preferably substituted with a least onefluoro atom. Suitable examples include, but are not limited to, —CF₃,—CH₂—CF₃, —CF₂—CF₂—CF₂—CF₃, and the like. Similarly, unless otherwisenoted, the term “fluorinated lower alkyl” refers to any lower alkylgroup as defined above substituted with at least one fluoro atom.Suitable examples include but are not limited to —CF₃, —CH₂—CF₃,—CF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, the term “hydroxy substitutedalkyl” refers to an alkyl group as defined above substituted with atleast one hydroxy group. Preferably, the alkyl group is substituted withone hydroxy group. Preferably, the hydroxy group is not bound at acarbon atom that is alpha to a nitrogen atom. More preferably, the alkylgroup is substituted with a hydroxy group at the terminal carbon.Suitable examples include, but are not limited to, —CH₂—OH, —CH₂—CH₂—OH,—CH₂—CH(OH)—CH₃, and the like.

As used herein, unless otherwise noted, “alkoxy” refers to an oxygenether radical of the above described straight or branched chain alkylgroups containing 1-8 carbon atoms. For example, methoxy, ethoxy,n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy, n-octyloxy and the like.

As used herein, unless otherwise noted, the term “halogenated loweralkoxy” refers to any lower alkoxy group as defined above substitutedwith at least one halogen atom, preferably substituted with a least onefluoro atom. Suitable examples include, but are not limited to, —OCF₃,—OCH₂—CF₃, —OCF₂—CF₂—CF₂—CF₃, and the like. Similarly, unless otherwisenoted, the term “fluorinated lower alkoxy” refers to any lower alkylgroup as defined above substituted with at least one fluoro atom.Suitable examples include but are not limited to —OCF₃, —OCH₂—CF₃,—OCF₂—CF₂—CF₂—CF₃, and the like.

As used herein, unless otherwise noted, the term “aryl” refers to ganunsaturated, aromatic monocyclic or bicyclic ring of 6 to 10 carbonmembers. Examples of aryl rings include phenyl and naphthyl.

As used herein, unless otherwise noted, the term “cycloalkyl” refers tosaturated or partially saturated, monocyclic, polycyclic, or bridgedhydrocarbon rings of 3 to 14 carbon atoms. Examples of such ringsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,1,2,3,4-tetrahydronaphthyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,and adamantyl.

As used herein, unless otherwise noted, “heteroaryl” refers to anaromatic monocyclic or bicyclic aromatic ring structure having 5 to 10ring members and which contains carbon atoms and from 1 to 4 heteroatomsindependently selected from the group consisting of N, O, and S.Included within the term heteroaryl are aromatic rings of 5 or 6 memberswherein the ring consists of carbon atoms and has at least oneheteroatom member. Suitable heteroatoms include nitrogen, oxygen, andsulfur. In the case of 5 membered rings, the heteroaryl ring preferablycontains one member of nitrogen, oxygen or sulfur and, in addition, upto three additional nitrogens. In the case of 6 membered rings, theheteroaryl ring preferably contains from one to three nitrogen atoms.For the case wherein the 6 membered ring has three nitrogens, at mosttwo nitrogen atoms are adjacent. Examples of heteroaryl groups includefuryl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl,isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl,pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. Unless otherwisenoted, the heteroaryl is attached to its pendant group at any heteroatomor carbon atom that results in a stable structure.

As used herein, unless otherwise noted, the term “heterocycloalkyl”refers to any five to seven membered monocyclic, saturated or partiallyunsaturated ring structure containing at least one heteroatom selectedfrom the group consisting of O, N and S, optionally containing one tothree additional heteroatoms independently selected from the groupconsisting of O, N and S; or a nine to ten membered saturated, partiallyunsaturated or partially aromatic bicyclic ring system containing atleast one heteroatom selected from the group consisting of O, N and S,optionally containing one to four additional heteroatoms independentlyselected from the group consisting of O, N and S. The heterocycloalkylgroup may be attached at any heteroatom or carbon atom of the ring suchthat the result is a stable structure.

Examples of suitable heterocycloalkyl groups include, but are notlimited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,indolinyl, chromenyl, 3,4-methylenedioxyphenyl, 2,3-dihydrobenzofuryl,and the like.

When a particular group is “substituted” (e.g., alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, etc.), that group may have one or moresubstituents, preferably from one to five substituents, more preferablyfrom one to three substituents, most preferably from one to twosubstituents, independently selected from the list of substituents.

With reference to substituents, the term “independently” means that whenmore than one of such substituents is possible, such substituents may bethe same or different from each other.

As used herein, the notation “*”denotes the presence of a stereogeniccenter.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similarly, wherein the compound is present as a diastereomer, thediastereomer is present at an diastereomeric excess of greater than orequal to about 80%, more preferably, at an diastereomeric excess ofgreater than or equal to about 90%, more preferably still, at andiastereomeric excess of greater than or equal to about 95%, morepreferably still, at an diastereomeric excess of greater than or equalto about 98%, most preferably, at an diastereomeric excess of greaterthan or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of thepresent invention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe present invention may form solvates with water (i.e., hydrates) orcommon organic solvents, and such solvates are also intended to beencompassed within the scope of this invention.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

Unless otherwise noted, for compounds of formula (I), the R¹ group shallbe denoted as bound to the 1-position, the R² group shall be denoted asbound at the 7-position and the R⁰ group(s) (which are bound to thebenzo-fused portion of the benzimidazole core) shall be denoted as boundto the 4-, 5- and/or 6-positions according to the following numberingconvention:

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

DCM=Dichloromethane

DMF=N,N-Dimethylformamide

DMSO=Dimethylsulfoxide

EtOAc=Ethyl acetate

HPLC=High Performance Liquid Chromatography

MeOH=Methanol

MTBE=Methyl-t-butyl ether

Pd/C=Palladium on Carbon

TEA=Triethylamine

TFA=Trifluoroacetic Acid

THF=Tetrahydrofuran

TRPM8=Transient Receptor Potential M8 channel

As used herein, unless otherwise noted, the terms “treating”,“treatment” and the like, shall include the management and care of asubject or patient (preferably mammal, more preferably human) for thepurpose of combating a disease, condition, or disorder and includes theadministration of a compound of the present invention to prevent theonset of the symptoms or complications, alleviate the symptoms orcomplications, or eliminate the disease, condition, or disorder.

As used herein, unless otherwise noted, the term “prevention” shallinclude (a) reduction in the frequency of one or more symptoms; (b)reduction in the severity of one or more symptoms; (c) delay oravoidance of the development of additional symptoms; and/or (d) delay oravoidance of the development of the disorder or condition.

One skilled in the art will recognize that wherein the present inventionis directed to methods of prevention, a subject in need thereof (i.e., asubject in need of prevention) shall include any subject or patient(preferably a mammal, more preferably a human) who has experienced orexhibited at least one symptom of the disorder, disease or condition tobe prevented. Further, a subject in need thereof may additionally be asubject (preferably a mammal, more preferably a human) who has notexhibited any symptoms of the disorder, disease or condition to beprevented, but who has been deemed by a physician, clinician or othermedical professional to be at risk of developing said disorder, diseaseor condition. For example, the subject may be deemed at risk ofdeveloping a disorder, disease or condition (and therefore in need ofprevention or preventive treatment) as a consequence of the subject'smedical history, including, but not limited to, family history,pre-disposition, co-existing (comorbid) disorders or conditions, genetictesting, and the like.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment. Preferably, the subject has experiencedand/or exhibited at least one symptom of the disease or disorder to betreated and/or prevented.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thesyndrome, disease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

For the purposes of the present invention, the term “antagonist” is usedto refer to a compound capable of producing, depending on thecircumstance, a functional antagonism of an ion channel, including, butnot limited to, competitive antagonists, non-competitive antagonists,desensitizing agonists, and partial agonists.

For purposes of the present invention, the term “TRPM8-modulated” isused to refer to the condition of being affected by the modulation ofthe TRPM8 channel, including but not limited to, the state of beingmediated by the TRPM8 channel.

As more extensively provided in this written description, terms such as“reacting” and “reacted” are used herein in reference to a chemicalentity that is any one of: (a) the actually recited form of suchchemical entity, and (b) any of the forms of such chemical entity in themedium in which the compound is being considered when named.

One skilled in the art will recognize that, where not otherwisespecified, the reaction step(s) is performed under suitable conditions,according to known methods, to provide the desired product. One skilledin the art will further recognize that, in the specification and claimsas presented herein, wherein a reagent or reagent class/type (e.g. base,solvent, etc.) is recited in more than one step of a process, theindividual reagents are independently selected for each reaction stepand may be the same of different from each other. For example whereintwo steps of a process recite an organic or inorganic base as a reagent,the organic or inorganic base selected for the first step may be thesame or different than the organic or inorganic base of the second step.Further, one skilled in the art will recognize that wherein a reactionstep of the present invention may be carried out in a variety ofsolvents or solvent systems, said reaction step may also be carried outin a mixture of the suitable solvents or solvent systems. One skilled inthe art will further recognize that wherein two consecutive reaction orprocess steps are run without isolation of the intermediate product(i.e. the product of the first of the two consecutive reaction orprocess steps), then the first and second reaction or process steps maybe run in the same solvent or solvent system; or alternatively may berun in different solvents or solvent systems following solvent exchange,which may be completed according to known methods.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about.” It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any rangetherein.

Examples of suitable solvents, bases, reaction temperatures, and otherreaction parameters and components are provided in the detaileddescriptions which follows herein. One skilled in the art will recognizethat the listing of said examples is not intended, and should not beconstrued, as limiting in any way the invention set forth in the claimswhich follow thereafter.

As used herein, unless otherwise noted, the term “aprotic solvent” shallmean any solvent that does not yield a proton. Suitable examplesinclude, but are not limited to DMF, 1,4-dioxane, THF, acetonitrile,pyridine, dichloroethane, dichloromethane, MTBE, toluene, acetone, andthe like.

As used herein, unless otherwise noted, the term “leaving group” shallmean a charged or uncharged atom or group which departs during asubstitution or displacement reaction. Suitable examples include, butare not limited to, Br, Cl, I, mesylate, tosylate, triflate, and thelike.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

As used herein, unless otherwise noted, the term “nitrogen protectinggroup” refers to a group which may be attached to a nitrogen atom toprotect said nitrogen atom from participating in a reaction and whichmay be readily removed following the reaction. Suitable nitrogenprotecting groups include, but are not limited to carbamates—groups ofthe formula —C(O)O—R wherein R is for example methyl, ethyl, t-butyl,benzyl, phenylethyl, CH₂═CH—CH₂—, and the like; amides—groups of theformula—C(O)—R′ wherein R′ is for example methyl, phenyl,trifluoromethyl, and the like; N-sulfonyl derivatives—groups of theformula —SO₂—R″ wherein R″ is for example tolyl, phenyl,trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-,2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogenprotecting groups may be found in texts such as T. W. Greene & P. G. M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

As used herein, unless otherwise noted, the term “oxygen protectinggroup” refers to a group which may be attached to a oxygen atom toprotect said oxygen atom from participating in a reaction and which maybe readily removed following the reaction. Suitable oxygen protectinggroups include, but are not limited to, acetyl, benzoyl,t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, THP, and the like.Other suitable oxygen protecting groups may be found in texts such as T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, JohnWiley & Sons, 1991.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-D-tartaric acid and/or(+)-di-p-toluoyl-L-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

Additionally, chiral HPLC against a standard may be used to determinepercent enantiomeric excess (% ee). The enantiomeric excess may becalculated as follows[(Rmoles−Smoles)/(Rmoles+Smoles)]×100%

where Rmoles and Smoles are the R and S mole fractions in the mixturesuch that Rmoles+Smoles=1. The enantiomeric excess may alternatively becalculated from the specific rotations of the desired enantiomer and theprepared mixture as follows:ee=([α−obs]/[α−max])×100.

One embodiment of the present invention is directed to a compositioncomprising the dextrorotatory enantiomer of a compound of formula (I)wherein said composition is substantially free from the levorotatoryisomer of said compound. In the present context, substantially freemeans less than 25%, preferably less than 10%, more preferably less than5%, even more preferably less than 2% and even more preferably less than1% of the levorotatory isomer calculated as

${\%\mspace{14mu}{dextrorotatory}} = {\frac{\left( {{mass}\mspace{14mu}{dextrorotatory}} \right)}{\left( {{mass}\mspace{14mu}{dextrorotatory}} \right) + \left( {{mass}\mspace{14mu}{levorotatory}} \right)} \times 100.}$

Another embodiment of the present invention is a composition comprisingthe levorotatory enantiomer of a compound of formula (I) wherein saidcomposition is substantially free from the dextrorotatory isomer of saidcompound. In the present context, substantially free from means lessthan 25%, preferably less than 10%, more preferably less than 5%, evenmore preferably less than 2% and even more preferably less than 1% ofthe dextrorotatory isomer calculated as

${\%\mspace{14mu}{levorotatory}} = {\frac{\left( {{mass}\mspace{14mu}{levorotatory}} \right)}{\left( {{mass}\mspace{14mu}{dextrorotatory}} \right) + \left( {{mass}\mspace{14mu}{levorotatory}} \right)} \times 100.}$

Embodiments of the present invention include prodrugs of compounds offormula (I). In general, such prodrugs will be functional derivatives ofthe compounds that are readily convertible in vivo into the requiredcompound. Thus, in the methods of treating or preventing embodiments ofthe present invention, the term “administering” encompasses thetreatment or prevention of the various diseases, conditions, syndromesand disorders described with the compound specifically disclosed or witha compound that may not be specifically disclosed, but which converts tothe specified compound in vivo after administration to a patient.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs”,ed. H. Bundgaard, Elsevier, 1985.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts include,but are not limited to, the following: acetate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calciumedetate, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: acids including acetic acid, 2,2-dichloroacetic acid,acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, (+)-camphoric acid, camphorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid,hydrobromic acid, hydrochloric acid, (+)-1-lactic acid, (±)-DL-lacticacid, lactobionic acid, maleic acid, (−)-1-malic acid, malonic acid,(±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid,naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotincacid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid,pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid,4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid,sulfuric acid, tannic acid, (+)-1-tartaric acid, thiocyanic acid,p-toluenesulfonic acid and undecylenic acid.

Representative bases that may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: bases including ammonia, L-arginine, benethamine, benzathine,calcium hydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,triethanolamine, tromethamine and zinc hydroxide.

Even though the compounds of embodiments of the present invention(including their pharmaceutically acceptable salts and pharmaceuticallyacceptable solvates) can be administered alone, they will generally beadministered in admixture with a pharmaceutically acceptable carrier, apharmaceutically acceptable excipient and/or a pharmaceuticallyacceptable diluent selected with regard to the intended route ofadministration and standard pharmaceutical or veterinary practice. Thus,particular embodiments of the present invention are directed topharmaceutical and veterinary compositions comprising compounds offormula (I) and at least one pharmaceutically acceptable carrier,pharmaceutically acceptable excipient, and/or pharmaceuticallyacceptable diluent.

By way of example, in the pharmaceutical compositions of embodiments ofthe present invention, the compounds of formula (I) may be admixed withany suitable binder(s), lubricant(s), suspending agent(s), coatingagent(s), solubilizing agent(s), and combinations thereof.

Solid oral dosage forms, such as tablets or capsules, containing thecompounds of the present invention may be administered in at least onedosage form at a time, as appropriate. It is also possible to administerthe compounds in sustained release formulations.

Additional oral forms in which the present inventive compounds may beadministered include elixirs, solutions, syrups, and suspensions; eachoptionally containing flavoring agents and coloring agents.

Alternatively, compounds of formula (I) can be administered byinhalation (intratracheal or intranasal) or in the form of a suppositoryor pessary, or they may be applied topically in the form of a lotion,solution, cream, ointment or dusting powder. For example, they can beincorporated into a cream comprising, consisting of, and/or consistingessentially of an aqueous emulsion of polyethylene glycols or liquidparaffin. They can also be incorporated, at a concentration of betweenabout 1% and about 10% by weight of the cream, into an ointmentcomprising, consisting of, and/or consisting essentially of a white waxor white soft paraffin base together with any stabilizers andpreservatives as may be required. An alternative means of administrationincludes transdermal administration by using a skin or transdermalpatch.

The pharmaceutical compositions of the present invention (as well as thecompounds of the present invention alone) can also be injectedparenterally, for example intracavernosally, intravenously,intramuscularly, subcutaneously, intradermally or intrathecally. In thiscase, the compositions will also include at least one of a suitablecarrier, a suitable excipient, and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of thepresent invention are best used in the form of a sterile aqueoussolution that may contain other substances, for example, enough saltsand monosaccharides to make the solution isotonic with blood.

For buccal or sublingual administration, the pharmaceutical compositionsof the present invention may be administered in the form of tablets orlozenges, which can be formulated in a conventional manner.

By way of further example, pharmaceutical compositions containing atleast one of the compounds of formula (I) as the active ingredient canbe prepared by mixing the compound(s) with a pharmaceutically acceptablecarrier, a pharmaceutically acceptable diluent, and/or apharmaceutically acceptable excipient according to conventionalpharmaceutical compounding techniques. The carrier, excipient, anddiluent may take a wide variety of forms depending upon the desiredroute of administration (e.g., oral, parenteral, etc.). Thus, for liquidoral preparations, such as suspensions, syrups, elixirs and solutions,suitable carriers, excipients and diluents include water, glycols, oils,alcohols, flavoring agents, preservatives, stabilizers, coloring agentsand the like; for solid oral preparations, such as powders, capsules andtablets, suitable carriers, excipients and diluents include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Solid oral preparations also may beoptionally coated with substances, such as, sugars, or be entericallycoated so as to direct the major site of absorption and disintegration.For parenteral administration, the carrier, excipient and diluent willusually include sterile water; however other ingredients may be added toincrease solubility and preservation of the composition. Injectablesuspensions or solutions may also be prepared utilizing aqueous carriersalong with appropriate additives, such as solubilizers andpreservatives.

A therapeutically effective amount of a compound of formula (I) or apharmaceutical composition thereof includes a dose range from about 0.1mg to about 3000 mg, in particular from about 1 mg to about 1000 mg or,more particularly, from about 10 mg to about 500 mg of active ingredientin a regimen of about 1 to 4 times per day for an average (70 kg) human;although, it is apparent to one skilled in the art that thetherapeutically effective amount for active compounds of the inventionwill vary as will the diseases, syndromes, conditions, and disordersbeing treated.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing about 1, about 10, about 50,about 100, about 150, about 200, about 250, and about 500 milligrams ofthe inventive compound as the active ingredient.

Advantageously, a compound of formula (I) may be administered in asingle daily dose, or the total daily dosage may be administered individed doses of two, three and four times daily.

Optimal dosages of a compound of formula (I) to be administered may bereadily determined and will vary with the particular compound used, themode of administration, the strength of the preparation, and theadvancement of the disease, syndrome, condition, or disorder. Inaddition, factors associated with the particular subject being treated,including subject age, weight, diet and time of administration, willresult in the need to adjust the dose to achieve an appropriatetherapeutic level. The above dosages are thus exemplary of the averagecase. There can be, of course, individual instances wherein higher orlower dosage ranges are merited, and such are within the scope of thisinvention.

Compounds of formula (I) may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of a compound offormula (I) is required for a subject in need thereof.

As antagonists of the TRPM8 channel, the compounds of formula (I) areuseful in methods for treating and preventing a disease, a syndrome, acondition, or a disorder in a subject, including an animal, a mammal anda human in which the disease, the syndrome, the condition, or thedisorder is affected by the modulation of TRPM8 channels. Such methodscomprise, consist of, and consist essentially of administering to asubject, including an animal, a mammal, and a human in need of suchtreatment or prevention a therapeutically effective amount of acompound, salt, or solvate of formula (I). In particular, the compoundsof formula (I) are useful for preventing or treating pain, or diseases,syndromes, conditions, or disorders causing such pain, or pulmonary orvascular dysfunction. More particularly, the compounds of formula (I)are useful for preventing or treating inflammatory pain, inflammatoryhypersensitivity conditions, neuropathic pain, anxiety, depression, andcardiovascular disease aggravated by cold, including peripheral vasculardisease, vascular hypertension, pulmonary hypertension, Raynaud'sdisease, and coronary artery disease, by administering to a subject inneed thereof a therapeutically effective amount of a compound of formula(I).

Examples of inflammatory pain include pain due to a disease, condition,syndrome, disorder, or a pain state including inflammatory boweldisease, visceral pain, migraine, post operative pain, osteoarthritis,rheumatoid arthritis, back pain, lower back pain, joint pain, abdominalpain, chest pain, labor, musculoskeletal diseases, skin diseases,toothache, pyresis, burn, sunburn, snake bite, venomous snake bite,spider bite, insect sting, neurogenic bladder, interstitial cystitis,urinary tract infection, rhinitis, contact dermatitis/hypersensitivity,itch, eczema, pharyngitis, mucositis, enteritis, irritable bowelsyndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome,menstrual pain, endometriosis, sinus headache, tension headache, orarachnoiditis.

One type of inflammatory pain is inflammatory hyperalgesia, which can befurther distinguished as inflammatory somatic hyperalgesia orinflammatory visceral hyperalgesia. Inflammatory somatic hyperalgesiacan be characterized by the presence of an inflammatory hyperalgesicstate in which a hypersensitivity to thermal, mechanical and/or chemicalstimuli exists. Inflammatory visceral hyperalgesia can also becharacterized by the presence of an inflammatory hyperalgesic state, inwhich an enhanced visceral irritability exists.

Examples of inflammatory hyperalgesia include a disease, syndrome,condition, disorder, or pain state including inflammation,osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominalpain, musculoskeletal diseases, skin diseases, post operative pain,headaches, toothache, burn, sunburn, insect sting, neurogenic bladder,urinary incontinence, interstitial cystitis, urinary tract infection,cough, asthma, chronic obstructive pulmonary disease, rhinitis, contactdermatitis/hypersensitivity, itch, eczema, pharyngitis, enteritis,irritable bowel syndrome, inflammatory bowel diseases including Crohn'sDisease or ulcerative colitis.

One embodiment of the present invention is directed to a method fortreating inflammatory somatic hyperalgesia in which a hypersensitivityto thermal, mechanical and/or chemical stimuli exists, comprising thestep of administering to a mammal in need of such treatment atherapeutically effective amount of a compound, salt or solvate offormula (I).

A further embodiment of the present invention is directed to a methodfor treating inflammatory visceral hyperalgesia in which an enhancedvisceral irritability exists, comprising, consisting of, and/orconsisting essentially of the step of administering to a subject in needof such treatment a therapeutically effective amount of a compound, saltor solvate of formula (I).

A further embodiment of the present invention is directed to a methodfor treating neuropathic cold allodynia in which a hypersensitivity to acooling stimuli exists, comprising, consisting of, and/or consistingessentially of the step of administering to a subject in need of suchtreatment a therapeutically effective amount of a compound, salt orsolvate of formula (I).

Examples of a neuropathic pain include pain due to a disease, syndrome,condition, disorder, or pain state including cancer, neurologicaldisorders, spine and peripheral nerve surgery, brain tumor, traumaticbrain injury (TBI), spinal cord trauma, chronic pain syndrome,fibromyalgia, chronic fatigue syndrome, neuralgias (trigeminalneuralgia, glossopharyngeal neuralgia, postherpetic neuralgia andcausalgia), lupus, sarcoidosis, peripheral neuropathy, bilateralperipheral neuropathy, diabetic neuropathy, central pain, neuropathiesassociated with spinal cord injury, stroke, amyotrophic lateralsclerosis (ALS), Parkinson's disease, multiple sclerosis, sciaticneuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis,stump pain, phantom limb pain, bony fractures, oral neuropathic pain,Charcot's pain, complex regional pain syndrome I and II (CRPS I/II),radiculopathy, Guillain-Barre syndrome, meralgia paresthetica,burning-mouth syndrome, optic neuritis, postfebrile neuritis, migratingneuritis, segmental neuritis, Gombault's neuritis, neuronitis,cervicobrachial neuralgia, cranial neuralgia, geniculate neuralgia,glossopharyngial neuralgia, migrainous neuralgia, idiopathic neuralgia,intercostals neuralgia, mammary neuralgia, Morton's neuralgia,nasociliary neuralgia, occipital neuralgia, red neuralgia, Sluder'sneuralgia, splenopalatine neuralgia, supraorbital neuralgia, vulvodynia,or vidian neuralgia.

One type of neuropathic pain is neuropathic cold allodynia, which can becharacterized by the presence of a neuropathy-associated allodynic statein which a hypersensitivity to cooling stimuli exists. Examples ofneuropathic cold allodynia include allodynia due to a disease,condition, syndrome, disorder or pain state including neuropathic pain(neuralgia), pain arising from spine and peripheral nerve surgery ortrauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpeticneuralgia, causalgia, peripheral neuropathy, diabetic neuropathy,central pain, stroke, peripheral neuritis, polyneuritis, complexregional pain syndrome I and II (CRPS I/II) and radiculopathy.

General Synthetic Methods

Compounds of formula (I) may be prepared according to the processoutlined in Scheme 1.

Accordingly, a suitably substituted compound of formula (V), a knowncompound or compound prepared by known methods, is reacted with cyanogenbromide, in an aqueous organic solvent such as methanol, ethanol,isopropanol, and the like, preferably at about room temperature, toyield the corresponding compound of formula (VI).

The compound of formula (VI) is reacted with a suitably substitutedcompound of formula (VII), a known compound or compound prepared byknown methods, in the presence of an organic base such as pyridine, TEA,and the like, neat or in an organic solvent such as THF, methylenechloride, chloroform, and the like, preferably at from about roomtemperature to about 60° C., to yield the corresponding compound offormula (VIII).

The compound of formula (VIII) is reacted with a suitably substitutedcompound of formula (IX), wherein LG¹ is a suitably selected leavinggroup such as Br, Cl, and the like, in the presence of an base,preferably an inorganic base, such as K₂CO₃, Na₂CO₃, pyridine, TEA, andthe like, in an organic solvent such as DMF, methylene chloride,acetonitrile, and the like, to yield a mixture of the correspondingcompound of formula (I) and the corresponding compound of formula (II).

Preferably the compound of formula (I) is separated from the mixture,according to known methods, for example by column chromatography, HPLC<and the like.

Compounds of formula (I) wherein R¹ and R² are not taken together toform a ring structure may alternatively be prepared according to theprocess outlined in Scheme 2.

Accordingly, a suitably substituted compound of formula (X), wherein LG²is a suitably selected leaving group such as Cl, Br, I, and the like, aknown compound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XI), a known compound orcompound prepared by known methods, neat or in an organic solvent suchas DMF, and the like, to yield the corresponding compound of formula(XII).

The compound of formula (XII) is reacted with a suitably substitutedcompound of formula (VII), a known compound or compound prepared byknown methods, in the presence of an organic base such as pyridine, TEA,and the like, neat or in an organic solvent such as THF, methylenechloride, chloroform, and the like, preferably at an elevatedtemperature of about 50° C. or under microwave heating, to yield thecorresponding compound of formula (I).

Compounds of formula (I) wherein R¹ and R² are not taken together toform a ring structure may alternatively be prepared according to theprocess outlined in Scheme 3.

Accordingly, a suitably substituted compound of formula (X), a knowncompound or compound prepared by known methods, is reacted with asuitably substituted compound of formula (XIII), a known compound orcompound prepared by known methods, in the presence of a base such asNaH, KH, and the like, in an organic solvent such as DMF, THF, and thelike, preferably at an elevated temperature of about 50° C. or undermicrowave heating, to yield the corresponding compound of formula (I).

During any of the processes for preparation of the compounds of thevarious embodiments of the present invention, it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, Second Edition, J. F. W. McOmie, Plenum Press, 1973;T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,John Wiley & Sons, 1991; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. Theprotecting groups may be removed at a convenient subsequent stage usingmethods known from the art.

Even though the compounds of embodiments of the present invention(including their pharmaceutically acceptable salts and pharmaceuticallyacceptable solvates) can be administered alone, they will generally beadministered in admixture with a pharmaceutically acceptable carrier, apharmaceutically acceptable excipient and/or a pharmaceuticallyacceptable diluent selected with regard to the intended route ofadministration and standard pharmaceutical or veterinary practice. Thus,particular embodiments of the present invention are directed topharmaceutical and veterinary compositions comprising compounds offormula (I) and at least one pharmaceutically acceptable carrier,pharmaceutically acceptable excipient, and/or pharmaceuticallyacceptable diluent.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trailsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

EXAMPLE 1N-(4-Fluoro-3-trifluoromethyl-benzyl)-N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide(Compound #15)

Step A: 2-Chloro-1-methyl-1H-benzimidazole

To a solution of 2-chloro-1H-benzimidazole (5.03 g, 33.0 mmol) inanhydrous DMF (33 mL) at 0° C. was added portion-wise 95% NaH (871 mg,36.3 mmol). The ice bath was removed and the resulting mixture wasstirred at room temperature for 1 h. Iodomethane (4.68 g, 33.0 mmol) wasadded and the resulting mixture was stirred at room temperatureovernight. The resulting mixture was then diluted with water, and theresulting precipitate was collected by filtration and purified byrecrystallization from hexane to yield2-chloro-1-methyl-1H-benzimidazole. MS 167 (M+1)⁺

Step B:(4-Fluoro-3-trifluoromethyl-benzyl)-(1-methyl-1H-benzimidazol-2-yl)-amine

A mixture of 2-chloro-1-methyl-1H-benzimidazole (915 mg, 5.5 mmol) and4-fluoro-3-trifluoromethyl-benzylamine (4.24 g, 22.0 mmol) was stirredat 130° C. overnight. The resulting mixture was diluted with EtOAc,washed with H₂O, dried over Na₂SO₄, filtered, and concentrated in vacuo.The resulting residue was purified by recrystallization from hexane toyield(4-fluoro-3-trifluoromethyl-benzyl)-(1-methyl-1H-benzimidazol-2-yl)-amineMS 324 (M+1)⁺

Step C:N-(4-Fluoro-3-trifluoromethyl-benzyl)-N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide

To(4-fluoro-3-trifluoromethyl-benzyl)-(1-methyl-1H-benzimidazol-2-yl)-amine(195 mg, 0.6 mmol) in anhydrous pyridine (3 mL) at room temperature wasadded benzenesulfonyl chloride (193 mg, 1.1 mmol). The resulting mixturewas heated to 100° C. in a microwave reactor for 1 h; then diluted withEtOAc, washed with 1 N HCl, the organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The resultant residue was purifiedby flash column chromatography (SiO₂), eluting with a hexanes-EtOAcgradient to yield the title compound. MS 464 (M+1)⁺

Compounds #17 (MS 402 (M+1)⁺), #18 (MS 478 (M+1)⁺) and #14 (MS 498(M+1)⁺) were similarly prepared according to the procedure as describedabove in Example 1, substituting suitably selected reagents, startingmaterials and purification methods known to those skilled in the art.

EXAMPLE 2N-(1-Methyl-1H-benzimidazol-2-yl)-N-(3-trifluoromethyl-benzyl)-benzenesulfonamide(Compound #12)

Step A: N-(1-Methyl-1H-benzimidazol-2-yl)-benzenesulfonamide

To a solution of 1-methyl-1H-benzimidazol-2-ylamine (2.65 g, 18.0 mmol)in anhydrous pyridine (15 mL) was added benzenesulfonyl chloride (2.30mL, 18.0 mmol). The resulting mixture was stirred at 60° C. for 1 day.After addition of water, a precipitate was obtained, a mixture ofN-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide andN-(1-benzenesulfonyl-3-methyl-1,3-dihydro-benzimidazol-2-ylidene)-benzenesulfonamide.The mixture was then treated with 1 N NaOH. The insoluble part of themixture was determined to beN-(1-benzenesulfonyl-3-methyl-1,3-dihydro-benzimidazol-2-ylidene)-benzenesulfonamide.The alkaline solution was acidified with acetic acid and the resultingsolid was collected by filtration, washed with H₂O and hexanes to yieldN-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide. MS 288 (M+1)⁺.

Step B:N-(1-Methyl-1H-benzimidazol-2-yl)-N-(3-trifluoromethyl-benzyl)-benzenesulfonamide

To a solution of N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide(100 mg, 0.35 mmol) in DMF (2 mL) was added1-bromomethyl-3-trifluoromethyl-benzene (166.4 mg, 0.70 mmol) andpotassium carbonate (48 mg). The resulting mixture was heated to 120° C.in a microwave reactor for 1 h. The resulting mixture was then dilutedwith EtOAc, washed with H₂O and the organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The resultant residue was purifiedby flash column chromatography (SiO₂), eluting with a hexanes-EtOAcgradient to yieldN-(1-methyl-1H-benzimidazol-2-yl)-N-(3-trifluoromethyl-benzyl)-benzenesulfonamide(1^(st) compound to elute off the column) MS 446 (M+1)⁺

The compounds of the present invention listed in Table 3 below weresimilarly prepared according to the procedure as described above inExample 2, substituting suitably selected reagents, starting materialsand purification methods known to those skilled in the art.

TABLE 3 Measured Mass Spec. ID No. MS (M + 1)⁺ 6 462 8 396 9 414 10 37811 446 13 462 19 478 20 430 21 464 22 464 23 444 24 488 26 496 27 530 28464 29 476 30 460 31 514 32 480 34 478 38 482 39 498 40 532 41 480 49504 50 506

EXAMPLE 3N-(1-Ethyl-5-fluoro-1H-benzimidazol-2-yl)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamide(Compound #47)

Step A: 1-Ethyl-5-fluoro-1H-benzoimidazol-2-ylamine

To a solution of N¹-ethyl-4-fluoro-benzene-1,2-diamine (1.54 g, 10.0mmol) in MeOH (20 mL) and H₂O (20 mL) was added cyanogen bromide (2.1mL, 10.5 mmol, 5.0 M in acetonitrile). The resulting mixture was stirredat room temperature overnight. The resulting mixture was then adjustedto pH>9 with concentrated NH₄OH and the resulting solid was collected byfiltration, washed with H₂O and hexanes to yield1-ethyl-5-fluoro-1H-benzimidazol-2-ylamine MS 180 (M+1)⁺.

Step B: N-(1-Ethyl-5-fluoro-1H-benzimidazol-2-yl)-benzenesulfonamide

N-(1-Ethyl-5-fluoro-1H-benzimidazol-2-yl)-benzenesulfonamide wasprepared according to the procedure as described in Example 2, STEP A,substituting 1-ethyl-5-fluoro-1H-benzimidazol-2-ylamine for1-methyl-1H-benzimidazol-2-ylamine. MS 320 (M+1)⁺

Step C:N-(1-Ethyl-5-fluoro-1H-benzimidazol-2-yl)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamide

N-(1-Ethyl-5-fluoro-1H-benzimidazol-2-yl)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamidewas prepared according to the procedure as described in Example 2, STEPB, substitutingN-(1-ethyl-5-fluoro-1H-benzimidazol-2-yl)-benzenesulfonamide forN-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide and furthersubstituting 1-bromomethyl-4-trifluoromethyl-benzene for1-bromomethyl-3-trifluoromethyl-benzene. MS 478 (M+1)⁺

The compounds of the present invention listed in Table 4 below weresimilarly prepared according to the procedure as described above inExample 3, substituting suitably selected reagents, starting materialsand purification methods known to those skilled in the art.

TABLE 4 Measured Mass Spec. ID No. MS (M + 1)⁺ 42 546 43 464 45 560 46494 47 480 48 496 51 514 52 530 53 532 56 526 58 482 61 524 62 488 63490 65 472

EXAMPLE 4N-(3-Fluoro-4-trifluoromethyl-benzyl)-N-[1-(2,2,2-trifluoro-ethyl)-1H-benzimidazol-2-yl]-benzenesulfonamide(Compound #60)

Step A: (2-Nitro-phenyl)-(2,2,2-trifluoro-ethyl)-amine

A mixture of 1-fluoro-2-nitro-benzene (1.55 g, 11.0 mmol),2,2,2-trifluoro-ethylamine (3.27 g, 33.0 mmol) and DMSO (4.5 mL) washeated at 120° C. for 24 h. The resulting mixture was poured ontoice/H₂O and the resultant precipitate was collected by filtration,washed with H₂O, and hexanes to yield(2-nitro-phenyl)-(2,2,2-trifluoro-ethyl)-amine MS 221 (M+1)⁺

Step B: N-(2,2,2-Trifluoro-ethyl)-benzene-1,2-diamine

To a solution of (2-nitro-phenyl)-(2,2,2-trifluoro-ethyl)-amine (2.16 g,9.8 mmol) in THF (6 mL) and MeOH (24 mL) at 0° C. was added ammoniumformate (2.47 g, 39.2 mmol). The resulting mixture was purged withnitrogen, then 10% Pd/C (57 mg) was added. The ice bath was removed andthe resulting mixture was stirred at room temperature for 5 h. Theresulting mixture was filtered over CELITE®, washing with EtOAc. Removalof the solvent in vacuo yieldedN-(2,2,2-trifluoro-ethyl)-benzene-1,2-diamine, which was used in thenext step without further purification. MS 191 (M+1)⁺

Step C: 1-(2,2,2-Trifluoro-ethyl)-1H-benzimidazol-2-ylamine

1-(2,2,2-Trifluoro-ethyl)-1H-benzimidazol-2-ylamine was preparedfollowing the procedure as described in Example 3, STEP A, substitutingN-(2,2,2-trifluoro-ethyl)-benzene-1,2-diamine forN¹-ethyl-4-fluoro-benzene-1,2-diamine MS 216 (M+1)⁺

Step D:N-[1-(2,2,2-Trifluoro-ethyl)-1H-benzimidazol-2-yl]-benzenesulfonamide

N-[1-(2,2,2-Trifluoro-ethyl)-1H-benzimidazol-2-yl]-benzenesulfonamidewas prepared according to the procedure as described in Example 2, STEPA, substituting 1-(2,2,2-trifluoro-ethyl)-1H-benzimidazol-2-ylamine for1-methyl-1H-benzimidazol-2-ylamine MS 356 (M+1)⁻

Step E:N-(3-Fluoro-4-trifluoromethyl-benzyl)-N-[1-(2,2,2-trifluoro-ethyl)-1H-benzimidazol-2-yl]-benzenesulfonamide

N-(3-Fluoro-4-trifluoromethyl-benzyl)-N-[1-(2,2,2-trifluoro-ethyl)-1H-benzimidazol-2-yl]-benzenesulfonamidewas prepared according to the procedure as described in Example 2, STEPB, substitutingN-[1-(2,2,2-trifluoro-ethyl)-1H-benzimidazol-2-yl]-benzensulfonamide forN-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide and furthersubstituting 4-bromomethyl-2-fluoro-1-trifluoromethyl-benzene for1-bromomethyl-3-trifluoromethyl-benzene. MS 532 (M+1)⁺

Compounds #54 (MS 514 (M+1)⁺) and #59 (MS 530 (M+1)⁺) were similarlyprepared according to the procedure as described above in Example 4,substituting suitably selected reagents, starting materials andpurification methods known to those skilled in the art.

EXAMPLE 5N-(1-Cyclopropylmethyl-1H-benzimidazol-2-yl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-benzenesulfonamide(Compound #71)

Step A: N-Cyclopropylmethyl-benzene-1,2-diamine

To a solution of benzene-1,2-diamine (1.62 g, 15.0 mmol) andcyclopropanecarbaldehyde (1.05 g, 15.0 mmol) in MeOH (15 mL) at 0° C.was added NaCNBH₃ (2.07 g, 33.0 mmol) and acetic acid (0.2 mL). The icebath was removed and the resulting mixture was stirred at roomtemperature overnight. The resulting mixture was then diluted withEtOAc, washed with H₂O, dried over Na₂SO₄, filtered, and concentrated invacuo. The resultant residue was purified by flash column chromatography(SiO₂), eluting with a hexanes-EtOAc gradient to yieldN-cyclopropylmethyl-benzene-1,2-diamine MS 163 (M+1)⁺

Step B: 1-Cyclopropylmethyl-1H-benzimidazol-2-ylamine

1-Cyclopropylmethyl-1H-benzimidazol-2-ylamine was prepared following theprocedure as described in Example 3, STEP A, substitutingN-cyclopropylmethyl-benzene-1,2-diamine forN¹-ethyl-4-fluoro-benzene-1,2-diamine MS 188 (M+1)⁺

Step C: N-(1-Cyclopropylmethyl-1H-benzimidazol-2-yl)-benzenesulfonamide

N-(1-Cyclopropylmethyl-1H-benzimidazol-2-yl)-benzenesulfonamide wasprepared according to the procedure as described in Example 2, STEP A,substituting 1-cyclopropylmethyl-1H-benzimidazol-2-ylamine for1-methyl-1H-benzimidazol-2-ylamine MS 328 (M+1)⁺

Step D:N-(1-Cyclopropylmethyl-1H-benzimidazol-2-yl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-benzenesulfonamide

N-(1-Cyclopropylmethyl-1H-benzimidazol-2-yl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-benzenesulfonamidewas prepared according to the procedure as described in Example 2, STEPB, substitutingN-(1-cyclopropylmethyl-1H-benzimidazol-2-yl)-benzenesulfonamide forN-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide and furthersubstituting 4-bromomethyl-2-fluoro-1-trifluoromethyl-benzene for1-bromomethyl-3-trifluoromethyl-benzene. MS 504 (M+1)⁺

Compounds #69 (MS 502 (M+1)⁺) and #70 (MS 486 (M+1)⁺) were similarlyprepared according to the procedure as described above in Example 5,substituting suitably selected reagents, starting materials andpurification methods known to those skilled in the art.

EXAMPLE 6N-(1,6-Dimethyl-1H-benzimidazol-2-yl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-benzenesulfonamide(Compound #67)

Step A: Methyl-(5-methyl-2-nitro-phenyl)-amine

To a solution of 5-methyl-2-nitro-phenylamine (3.04 g, 20.0 mmol) inanhydrous DMF (20 mL) at 0° C. was portionwise added 95% NaH (528 mg,22.0 mmol) and stirred for 10 min. A solution of iodomethane (1.25 mL,20.0 mmol) in anhydrous DMF (10 mL) was then added. The ice bath wasremoved and the resulting mixture was stirred at room temperatureovernight. The resulting mixture was then diluted with water, and theresulting solid was collected by filtration, washed with H₂O and hexanesto yield methyl-(5-methyl-2-nitro-phenyl)-amine MS 167 (M+1)⁺.

Step B: 4,N²-Dimethyl-benzene-1,2-diamine

To a solution of methyl-(5-methyl-2-nitro-phenyl)-amine (2.47 g, 14.9mmol), ammonium formate (15 g, 237.9 mmol) in THF (7 mL) and MeOH (35mL) at room temperature was added 10% Pd/C (650 mg) and the resuitngmixture was stirred at room temperature for 10 min. The resultingmixture was then filtered over CELITE® and concentrated in vacuo. Theresulting residue was diluted with CH₂Cl₂, washed with H₂O and theorganic layer dried over Na₂SO₄, filtered, and concentrated in vacuo.The resultant residue was purified by flash column chromatography(SiO₂), eluting with a hexanes-EtOAc gradient to yield4,N²-dimethyl-benzene-1,2-diamine

Step C: 1,6-Dimethyl-1H-benzimidazol-2-ylamine

1,6-Dimethyl-1H-benzimidazol-2-ylamine was prepared following theprocedure as described in Example 3, STEP A, substituting4,N²-dimethyl-benzene-1,2-diamine forN¹-ethyl-4-fluoro-benzene-1,2-diamine. MS 162 (M+1)⁺

Step D: N-(1,6-Dimethyl-1H-benzimidazol-2-yl)-benzenesulfonamide

N-(1,6-Dimethyl-1H-benzimidazol-2-yl)-benzenesulfonamide was preparedaccording to the procedure as described in Example 2, STEP A,substituting 1,6-dimethyl-1H-benzimidazol-2-ylamine for1-methyl-1H-benzimidazol-2-ylamine MS 302 (M+1)⁺

Step E:N-(1,6-Dimethyl-1H-benzimidazol-2-yl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-benzenesulfonamide

N-(1,6-Dimethyl-1H-benzimidazol-2-yl)-N-(3-fluoro-4-trifluoromethyl-benzyl)-benzenesulfonamidewas prepared according to the procedure as described in Example 2, STEPB, substituting N-(1,6-dimethyl-1H-benzimidazol-2-yl)-benzenesulfonamidefor N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide and furthersubstituting 4-bromomethyl-2-fluoro-1-trifluoromethyl-benzene for1-bromomethyl-3-trifluoromethyl-benzene. MS 478 (M+1)⁺

The compounds of the present invention listed in Table 5 below weresimilarly prepared according to the procedure as described above inExample 6, substituting suitably selected reagents, starting materialsand purification methods known to those skilled in the art.

TABLE 5 Measured Mass Spec. ID No. MS (M + 1)⁺ 33 530 35 532 37 514 66476 68 460 74 490 75 492 76 478

EXAMPLE 7N-(3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamideTFA salt (Compound #72)

Step A: 3,4-Dihydro-2H-benzo[1,4]oxazin-5-ylamine

3,4-Dihydro-2H-benzo[1,4]oxazin-5-ylamine was prepared according to theprocedure as described in Example 6, STEP B, substituting5-nitro-3,4-dihydro-2H-benzo[1,4]oxazine formethyl-(5-methyl-2-nitro-phenyl)-amine MS 151 (M+1)⁺

Step B: 3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-ylamine

3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-ylamine was preparedaccording to the procedure as described in Example 3, STEP A,substituting 3,4-dihydro-2H-benzo[1,4]oxazin-5-ylamine forN¹-ethyl-4-fluoro-benzene-1,2-diamine MS 176 (M+1)⁻

Step C:N-(3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-benzenesulfonamide

N-(3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-benzenesulfonamidewas prepared according to the procedure as described in Example 2, STEPA, substituting 3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-ylamine for1-methyl-1H-benzimidazol-2-ylamine MS 316 (M+1)⁺

Step D:N-(3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamidetrifluoroacetic acid salt

To a solution ofN-(3,4-Dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-benzenesulfonamide(125 mg, 0.40 mmol) in DMF (2.5 mL) was added1-bromomethyl-4-trifluoromethyl-benzene (190 mg, 0.80 mmol) andpotassium carbonate (55 mg). The resulting mixture was heated to 120° C.in a microwave reactor for 1 h. The resulting mixture was then dilutedwith EtOAc, washed with H₂O and the organic layer was dried over Na₂SO₄,filtered, and concentrated in vacuo. The resultant residue was purifiedby flash column chromatography (SiO₂), eluting with a hexanes-EtOAcgradient to yieldN-(3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamideas a crude residue (1^(st) compound to elute off the column) The residuewas purified by HPLC (reverse phase C-18 column, 45-100%acetonitrile/water containing 0.05% trifluoroacetic acid) to yieldN-(3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-N-(4-trifluoromethyl-benzyl)-benzenesulfonamideas its corresponding TFA salt. MS 474 (M+1)⁺

Compound #73 (MS 490 (M+1)⁺) was similarly prepared according to theprocedure as described above in Example 7, substituting suitablyselected reagents, starting materials and purification methods known tothose skilled in the art.

EXAMPLE 8N-(4-Chloro-phenyl)-N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide(Compound #36)

To (4-chloro-phenyl)-(1-methyl-1H-benzimidazol-2-yl)-amine (258 mg, 1.0mmol) in anhydrous pyridine (4 mL) at room temperature was addedbenzenesulfonyl chloride (706.5 mg, 4.0 mmol). The resulting mixture washeated to 100° C. in a microwave reactor for 1 h. The resulting mixturewas then diluted with EtOAc, washed with 1 N HCl and the organic layerwas dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresultant residue was purified by flash column chromatography (SiO₂),eluting with a hexanes-EtOAc gradient to yield the title compound as acrude residue, which was dissolved in ether containing 2.0M hydrogenchloride, and then concentrated in vacuo to yield the title compound asits corresponding HCl salt. MS 398 (M+1)⁺

EXAMPLE 9 N-Butyl-N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide(Compound #4)

Sodium hydride (0.029 g, 0.0012 mol, 1.1 equiv) was suspended in DMF (5mL). N-Butyl-benzenesulfonamide (0.256 g, 0.222 mL, 0.0012 mol. 1.2equiv) was then added and stirred at room temperature for 10 minutes. Tothe resulting mixture was then added the 2-chloro-N-methylbenzimidazole, (0.166 g, 0.001 mol). The resulting mixture was heated to50° C. and stirred overnight (16 hours). The resulting mixture was thenpoured into water (15 mL) and stirred for 1 hour. The resulting solutionwas extracted with DCM (20 mL) and the organic layer was separated. Theorganic layer was washed with 1N NaOH (20 mL), and brine (20 mL), thendried over Na₂SO₄ and evaporated under reduced pressure. The resultingresidue was purified by reverse phase HPLC (eluent 60-80% acetonitrile)to yield the title compound as a yellowish solid. MS 343.4

EXAMPLE 10

Compounds #1, 2 and 3, as shown below,

also known asN-(1-benzyl-1H-benzimidazol-2-yl)-N-butyl-benzenesulfonamide;

also known asN-butyl-N-[1-(2-hydroxy-ethyl)-1H-benzimidazol-2-yl]-benzenesulfonamide;and

also known asN-methyl-N-(1-methyl-1H-benzimidazol-2-yl)-benzenesulfonamide;

were similarly prepared according to the procedures as described herein.

BIOLOGICAL EXAMPLE 1 In Vitro Canine TRPM8 Functional Assay

The functional activity of representative compounds of the formula (I)of the present invention was quantified by measuring changes inintracellular calcium concentration using a Ca²⁺-sensitive fluorescentdye. The changes in fluorescent signal were monitored by a fluorescenceplate reader, either a FLIPR™ (Molecular Devices) or FDSS (Hamamatsu).Increases in intracellular Ca²⁺ concentration were readily detected uponactivation with icilin.

HEK293 cells stably expressing canine TRPM8 were routinely grown asmonolayers in Dulbecco's minimum essential medium supplemented with 10%FBS, 2 mM L-glutamine, 100 units/mL penicillin, 100 ug/mL streptomycinand 400 μg/mL G418. Cells were maintained in 5% CO₂ at 37° C. At 24 hrprior to assay, cells were seeded in black wall, clear-basepoly-D-lysine coated 384-well plates (BD Biosciences, NJ, USA) at adensity of 5,000 cells per well in culture medium and grown overnight in5% CO₂ at 37° C. On assay day, growth media was removed, and cells wereloaded with Calcium 3 Dye (Molecular Devices) for 35 min at 37° C.,under 5% CO₂ and then incubated for 25 min at room temperature andatmosphere. Subsequently, cells were tested for agonist-inducedincreases in intracellular Ca²⁺ levels using FLIPR™ or FDSS. Cells weretreated with compounds of the formula (I) at varying concentrations andintracellular Ca²⁻ was measured for 5 min prior to the addition oficilin to all wells to achieve a final concentration that producesapproximately an 80% maximal response. EC₅₀ or IC₅₀ values for compoundsof the present invention were determined from eight-pointconcentration-response studies and represent the concentration ofcompound required to elicit or inhibit 50% of the maximal response,respectively.

Maximal fluorescence intensity (FI) achieved upon addition of icilin wasexported from the FLIPR or FDSS software and further analyzed usingGraphPad Prism 3.02 (Graph Pad Software Inc., CA, U.S.A.). Basal FI wassubtracted prior to normalizing data to percent of maximal response.Curves were generated using the average of quadruplicate wells for eachdata point using nonlinear regression of either sigmoidal dose responseor sigmoidal dose response (variable slope). Finally, the EC₅₀ and IC₅₀values were calculated with the best-fit curve determined by GraphPadPrism

Representative compounds of the present invention were tested accordingto the procedures as described in Biological Example 1 above, withresults as listed in Table 6, below.

TABLE 6 Biological Activity Results ID No IC₅₀ (μM) % Inh @ 0.2 μM 1 192 11 3 9 4 0.041 92 6 0.001, 0.002 101, 100 8 0.004 101 9 0.002 101 100.008 101 11 0.002 101 12 0.003 102 13 0.003 101 14 0.030 97 15 0.001,0.004 102, 98 17 0.005 99 18 0.014 106 19 0.001 101 20 0.001 101 210.001 102 22 0.006 102 23 0.002 102 24 0.077 71 26 0.011 102 27 0.049101 28 0.006 95 29 0.005 95 30 0.004 96 31 0.033 96 32 0.006 94 33 340.007 102 35 36 0.033 94 37 38 0.011 102 39 0.010 102 40 0.060 101 410.009 102 42 43 0.004 100 44 45 46 47 0.006 100 48 0.007 100 49 0.048 8150 0.037 82 51 52 53 54 0.015, 0.075 85, 85 56 0.024 96 57 0.009 99 580.006 99 59 0.077 76 60 0.027 89 61 0.047 96 62 0.019 100 63 0.022 10165 0.017 101 66 0.021 98 67 0.022 98 68 0.024 99 69 0.026 101 70 0.035101 71 0.037 101 72 0.022 99 73  0.0034 99 74 0.019 99 75 0.028 101 76 0.0094 101

Compound #3 was re-tested according to the procedure as described above.Test samples were prepared by diluting a 10 mM stock solution ofcompound #3 with 100% DMSO prior to addition to assay buffer. Compound#3 exhibited 101% inhibition of at 1 μM and a calculated IC₅₀ of 0.094μM.

BIOLOGICAL EXAMPLE 2

Icilin was initially developed as a “super-cooling” compound by DelmarChemicals Ltd. Subsequently it was shown to be one of the most potentknown agonists of TRPM8 (McKemy D D, et al. Nature 2002, 416(6876):52-8), having an EC₅₀=0.2 μM in stimulating calcium ion influx intoTRPM8 transfected cells (Behrendt H J et al. Brit J Pharmacol 2004,141(4): 737-45). Initial in vivo testing of icilin showed it to cause“wet-dog” shakes in rats. Similar shaking or jumping behavior was alsoevident in mice, rabbits, cats, dogs and monkeys. In humans, icilinproduced a sensation of coolness on contact with mucous membranes, coldprickling when 0.1 mg was dropped on the tongue and coldness in themouth, pharynx and chest lasting 30-60 minutes when 5-10 mg was ingestedorally (Wei E T, Seid D A, J Pharm Pharmacol. 1983, 35, 110). Theinhibition or reversal of icilin-induced shaking behaviors in rodentsprovides evidence for the utility of TRPM8 antagonists in treating orpreventing a disease or condition in a mammal in which the disease orcondition is affected by the modulation of TRPM8 receptors.

Inhibition of Icilin-induced “Wet-dog” Shakes in Rats

Male Sprague Dawley rats (2200-450 g, Charles River Labs,n=6-9/treatment) were used to evaluate the ability of test compounds toblock icilin-induced “wet-dog” shakes (WDS). The test compound wasadministered in an appropriate vehicle, such ashydroxypropyl-β-cyclodextrin (HP-β-CD), methocellulose, 10% Solutol, H₂Oor the like, by the appropriate route (e.g., i.p. or p.o.), 30-60 minbefore icilin. Icilin was then administered in PEG-400 or 10%solutol/H₂O, at 1.0 or 3.0 mg/kg, i.p. and spontaneous “wet-dog” shakeswere counted 10-20 min post-icilin.

Representative compounds of the present invention were tested at 10mg/kg p.o. and 60 min pre-incilin, according to the procedure asdescribed above. Results, as listed in Table 7 below, are presented as apercent inhibition of shakes, which was calculated as [1−(test compoundWDS count/vehicle WDS count)]×100.

TABLE 7 Inhibition of icilin-induced “wet-dog” shakes in rats ID No.Vehicle % Inhibition 6  10% Solutol 20.2 15  10% Solutol 27.7 20  10%Solutol 32.6 47 0.5% HPMC 36 54  10% Solutol 2.4

Solid Oral Dosage Formulation Example

As a specific embodiment of an oral composition, 100 mg of the Compound#15, prepared as in Example 1, is formulated with sufficient finelydivided lactose to provide a total amount of 580 to 590 mg to fill asize O hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

1. A compound of formula (I),

wherein a is an integer form 0 to 1; R⁰ is selected from the groupconsisting of fluoro and methyl; R² is hydrogen; R¹ is selected from thegroup consisting of methyl and ethyl; alternatively R² and R¹ are takentogether as

R³ is selected from the group consisting of methyl, phenyl,4-fluorophenyl and 4-chlorophenyl; R⁴ is selected from the groupconsisting of benzyl, 4-fluoro-benzyl, 3,4-difluoro-benzyl,3-trifluoromethyl-benzyl, 4-trifluoromethyl-benzyl,4-difluoromethoxy-benzyl, 3-trifluoromethoxy-benzyl,4-trifluoromethoxy-benzyl, 3-chloro-4-fluoro-benzyl,3-trifluoromethyl-4-fluoro-benzyl, 3-fluoro-4-trifluoromethyl-benzyl,2-fluoro-5-trifluoromethyl-benzyl and 4-trilfuoromethyl-thio-benzyl; orpharmaceutically acceptable salt thereof.
 2. A compound as in claim 1,wherein a is an integer form 0 to 1; R⁰ is selected from the groupconsisting of fluoro and methyl; R² is hydrogen; R¹ is methyl;alternatively R² and R¹ are taken together as

R³ is phenyl; R⁴ is selected from the group consisting of4-fluoro-benzyl, 3,4-difluoro-benzyl, 3-trifluoromethyl-benzyl,4-trifluoromethyl-benzyl, 4-difluoromethoxy-benzyl,3-trifluoromethoxy-benzyl, 4-trifluoromethoxy-benzyl,3-chloro-4-fluoro-benzyl, 3-trifluoromethyl-4-fluoro-benzyl,3-fluoro-4-trifluoromethyl-benzyl and 4-trilfuoromethyl-thio-benzyl; orpharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of claim 2.